ES2888298T3 - Compuestos de C5-anilinoquinazolina y su uso en el tratamiento de cáncer - Google Patents

Compuestos de C5-anilinoquinazolina y su uso en el tratamiento de cáncer Download PDF

Info

Publication number: ES2888298T3
Authority: ES; Spain
Prior art keywords: triazol; compound; amino; acetamide; phenyl
Prior art date: 2017-04-27
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Active

Application number

ES18721348T

Other languages

English (en)

Spanish (es)

Inventor

Tudor Grecu

Jason Kettle

Martin Packer

Stuart Pearson

James Smith

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

AstraZeneca AB

Original Assignee

AstraZeneca AB

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2017-04-27

Filing date

2018-04-26

Publication date

2022-01-03

2018-04-26 Application filed by AstraZeneca AB filed Critical AstraZeneca AB

2022-01-03 Application granted granted Critical

2022-01-03 Publication of ES2888298T3 publication Critical patent/ES2888298T3/es

Status Active legal-status Critical Current

2038-04-26 Anticipated expiration legal-status Critical

Links

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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Epidemiology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)

ES18721348T 2017-04-27 2018-04-26 Compuestos de C5-anilinoquinazolina y su uso en el tratamiento de cáncer Active ES2888298T3 (es)

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US201762490859P	2017-04-27	2017-04-27
PCT/EP2018/060798 WO2018197642A1 (fr)	2017-04-27	2018-04-26	Composés de c5-anilinoquinazoline et leur utilisation dans le traitement du cancer

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US (2)	US10273227B2 (fr)
EP (1)	EP3615522B1 (fr)
JP (1)	JP7128204B2 (fr)
KR (1)	KR102603153B1 (fr)
CN (1)	CN110573505B (fr)
AR (1)	AR111494A1 (fr)
AU (1)	AU2018259078B2 (fr)
CA (1)	CA3059283A1 (fr)
ES (1)	ES2888298T3 (fr)
MX (1)	MX389244B (fr)
RU (1)	RU2769694C2 (fr)
TW (1)	TWI774758B (fr)
WO (1)	WO2018197642A1 (fr)

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AU2018259078B2 (en) *	2017-04-27	2021-10-07	Astrazeneca Ab	C5-anilinoquinazoline compounds and their use in treating cancer
WO2020078453A1 (fr) *	2018-10-18	2020-04-23	Sinomab Bioscience Limited	Méthodes de traitement de la polyarthrite rhumatoïde
AR117788A1 (es) *	2019-01-14	2021-08-25	Pi Industries Ltd	Compuestos de fenilamidina 3-sustituida, preparación y uso
MX2022013797A (es)	2020-05-08	2022-11-30	Genmab As	Anticuerpos biespecificos contra cd3 y cd20.
WO2022040341A1 (fr) *	2020-08-20	2022-02-24	The Board Of Trustees Of The Leland Stanford Junior University	Thérapie abscopale contre le cancer
MX2023002542A (es)	2020-09-10	2023-03-15	Genmab As	Anticuerpo biespecifico contra cumulo de difirenciacion 3 (cd3) y cumulo de difirenciacion 20 (cd20) en terapia combinada para el tratamiento del linfoma difuso de celulas b grandes.
BR112023004351A2 (pt)	2020-09-10	2023-04-04	Genmab As	Método para tratar linfoma folicular em um sujeito humano
IL301096A (en)	2020-09-10	2023-05-01	Genmab As	Bispecific antibodies against cd3 and cd20 for treating chronic lymphocytic leukemia
CA3189883A1 (fr)	2020-09-10	2022-03-17	Brian Elliott	Anticorps bispecifique contre cd3 et cd20 en polytherapie de traitement d'un lymphome folliculaire
EP4210747A1 (fr)	2020-09-10	2023-07-19	Genmab A/S	Anticorps bispécifique contre cd3 et cd20 en polythérapie pour le traitement un lymphome diffus à grandes cellules b
CN119137104A (zh) *	2021-12-09	2024-12-13	德西费拉制药有限责任公司	杂环化合物作为kit激酶抑制剂
WO2025188669A1 (fr) *	2024-03-04	2025-09-12	Cardiff Oncology, Inc.	Utilisation d'un inhibiteur de plk1 en tant que monothérapie et en combinaison avec du cétuximab dans le traitement du cancer colorectal de type sauvage ras

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB9510757D0 (en)	1994-09-19	1995-07-19	Wellcome Found	Therapeuticaly active compounds
GB9514265D0 (en)	1995-07-13	1995-09-13	Wellcome Found	Hetrocyclic compounds
US7709479B1 (en)	1999-09-21	2010-05-04	Astrazeneca	Quinazoline derivatives and their use as pharmaceuticals
PL209822B1 (pl)	2001-04-27	2011-10-31	Kirin Pharma Kk	Pochodna chinoliny lub chinazoliny, zawierająca ją kompozycja farmaceutyczna i zastosowanie
TW200505452A (en) *	2003-06-17	2005-02-16	Astrazeneca Ab	Chemical compounds
US7750160B2 (en) *	2003-11-13	2010-07-06	Ambit Biosciences Corporation	Isoxazolyl urea derivatives as kinase modulators
MX2007004403A (es)	2004-10-12	2007-04-27	Astrazeneca Ab	Derivados de quinazolina.
JO2787B1 (en)	2005-04-27	2014-03-15	امجين إنك,	Alternative amide derivatives and methods of use
US20070106549A1 (en)	2005-11-04	2007-05-10	Stocking Christine A	Turnkey aviation budget management
UY30183A1 (es)	2006-03-02	2007-10-31	Astrazeneca Ab	Derivados de quinolina
US20080194557A1 (en)	2007-01-18	2008-08-14	Joseph Barbosa	Methods and compositions for the treatment of pain, inflammation and cancer
US20080200458A1 (en)	2007-01-18	2008-08-21	Joseph Barbosa	Methods and compositions for the treatment of body composition disorders
TWI377944B (en) *	2007-06-05	2012-12-01	Hanmi Holdings Co Ltd	Novel amide derivative for inhibiting the growth of cancer cells
US20110104161A1 (en)	2008-05-14	2011-05-05	Burgess Teresa L	Combinations vegf(r) inhibitors and hepatocyte growth factor (c-met) inhibitors for the treatment of cancer
WO2011153553A2 (fr)	2010-06-04	2011-12-08	The Regents Of The University Of California	Méthodes et compositions pour l'inhibition de kinases
CN102532042A (zh)	2010-12-30	2012-07-04	上海医药工业研究院	一种芳基脲类化合物、其中间体及其应用
WO2012155339A1 (fr) *	2011-05-17	2012-11-22	江苏康缘药业股份有限公司	Dérivés de la 4-phénylamino-6-buténamide-7-alkyloxy quinazoline, leur procédé de préparation et leur utilisation
CN103254142B (zh)	2013-04-26	2015-10-28	浙江工业大学	4-[4-(2-取代氨基乙酰氨基)苯胺基]喹唑啉类衍生物及制备和应用
WO2014181287A1 (fr)	2013-05-09	2014-11-13	Piramal Enterprises Limited	Composés hétérocyclyliques et leurs utilisations
CN104130200B (zh)	2014-07-01	2016-04-20	中山大学	一种2-取代苯基-4-芳胺基喹唑啉衍生物及其制备方法和应用
JP7117323B2 (ja)	2017-04-27	2022-08-12	アストラゼネカ・アクチエボラーグ	フェノキシキナゾリン化合物及び癌の処置におけるそれらの使用
AU2018259078B2 (en) *	2017-04-27	2021-10-07	Astrazeneca Ab	C5-anilinoquinazoline compounds and their use in treating cancer

2018
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- 2018-04-26 EP EP18721348.3A patent/EP3615522B1/fr active Active
- 2018-04-26 CN CN201880027620.0A patent/CN110573505B/zh active Active
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AR111494A1 (es)	2019-07-17
MX2019012847A (es)	2022-01-07
RU2769694C2 (ru)	2022-04-05
US20180312490A1 (en)	2018-11-01
EP3615522A1 (fr)	2020-03-04
RU2019136279A3 (fr)	2021-05-31
AU2018259078A1 (en)	2019-10-17
MX389244B (es)	2025-03-20
CN110573505A (zh)	2019-12-13
JP2020517677A (ja)	2020-06-18
US20190263787A1 (en)	2019-08-29
WO2018197642A1 (fr)	2018-11-01
CA3059283A1 (fr)	2018-11-01
BR112019022229A2 (pt)	2020-05-12
RU2019136279A (ru)	2021-05-27
KR20190141203A (ko)	2019-12-23
TWI774758B (zh)	2022-08-21
CN110573505B (zh)	2023-04-11
TW201904960A (zh)	2019-02-01
EP3615522B1 (fr)	2021-08-04
US10273227B2 (en)	2019-04-30
AU2018259078B2 (en)	2021-10-07
KR102603153B1 (ko)	2023-11-15
US10829479B2 (en)	2020-11-10
JP7128204B2 (ja)	2022-08-30

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